HIV This Week

Buchbinder, SP, Mehrotra, DV, Duerr, A, Fitzgerald, DW, Mogg, R, Li, D, Gilbert, PB, Lama, JR, Marmor, M, del Rio, C, McElrath, MJ, Casimiro, DR, Gottesdiener, KM, Chodakewitz, JA, Corey,L, Robertson, MN, and the Step Study Protocol Team*. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial Lancet 2008 Epub

Observational data and non-human primate challenge studies suggest that cell-mediated immune responses might provide control of HIV replication. The Step Study directly assessed the efficacy of a cell-mediated immunity vaccine to protect against HIV-1 infection or change in early plasma HIV-1 levels. Buchbinder and colleagues undertook a double-blind, phase II, test-of-concept study at 34 sites in North America, the Caribbean, South America, and Australia. They randomly assigned 3000 HIV-1-seronegative participants by computer-generated assignments to receive three injections of MRKAd5 HIV-1 gag/pol/nef vaccine (n=1494) or placebo (n=1506). Randomisation was pre-stratified by sex, adenovirus type 5 (Ad5) antibody titre at baseline, and study site. Primary objective was a reduction in HIV-1 acquisition rates (tested every 6 months) or a decrease in HIV-1 viral-load setpoint ( early plasma HIV-1 RNA measured 3 months after HIV-1 diagnosis). Analyses were per protocol and modified intention to treat. The study was stopped early because it unexpectedly met the pre-specified futility boundaries at the first interim analysis. This study is registered with ClinicalTrials.gov, number NCT00095576. In a pre-specified interim analysis in participants with baseline Ad5 antibody titre 200 or less, 24 (3%) of 741 vaccine recipients became HIV-1 infected versus 21 (3%) of 762 placebo recipients (hazard ratio [HR] 1·2 [95% CI 0·6–2·2]). All but one infection occurred in men. The corresponding geometric mean plasma HIV-1 RNA was comparable in infected male vaccine and placebo recipients (4·61 vs 4·41 log10 copies per mL, one tailed p value for potential benefit 0·66). The vaccine elicited interferon-γ ELISPOT responses in 75% (267) of the 25% random sample of all vaccine recipients (including both low and high Ad5 antibody titres) on whose specimens this testing was done (n=354). In exploratory analyses of all study volunteers, irrespective of baseline Ad5 antibody titre, the hazard ratio of HIV-1 infection between vaccine and placebo recipients was higher in Ad5 seropositive men (hazard ratio 2·3 [95% CI 1·2–4·3]) and uncircumcised men (3·8 [1·5–9·3]), but was not increased in Ad5 seronegative (1·0 [0·5–1·9]) or circumcised (1·0 [0·6–1·7]) men.

Editors’ note: This study was stopped for futility, not safety, when the first interim analysis showed that, even if it had gone its full course, the trial would have not been able to prove or disprove the hypothesis that the vaccine could prevent infection and/or lower viral set point in those that did become infected. Further analyses showed that uncircumcised men in the vaccine arm, particularly if they reported unprotected insertive anal sex, were more likely to seroconvert, as were men who had high levels of antibodies to adenovirus 5, a common virus used as a vaccine vector. The vaccine did not infect them but rather seemed to increase their risk of becoming infected when exposed to HIV. Many questions are being asked about mucosal immune responses and pre-existing vector immunity but confounding due to herpes simplex virus 2, host genetic factors, or sexual network clustering has not been ruled out and is under study.